Normal human body temperature, also known as normothermia or euthermia, depends upon the place in the body at which the measurement is made, and the time of day and level of activity of the person. Different parts of the body have different temperatures. Measurements taken directly inside the body cavity are typically slightly higher than oral measurements, and oral measurements are somewhat higher than skin temperature. A commonly accepted average core body temperature (taken internally) is 37.0 C (98.6° F.). A typical oral (under the tongue) measurement is 36.8±0.7 C, or 98.2±1.3 F.
The use of intentional cooling to reduce body temperature, which creates a state of hypothermia, has application, for example, to slow metabolic processes and reduce oxygen demand, which can be beneficial during medical procedures, such as heart surgery.
The use of heat to create an elevated body temperature, i.e. hyperthermia, as a means of treating cancer and other diseases has been known and studied since ancient time. More recently, hyperthermia has been reported to be beneficial in treatment of a number of conditions, including: cancer, HIV/AIDS, Hepatitis C, chronic inflammatory conditions such as ulcerative colitis and Crohn's disease, rheumatic conditions, bronchial asthma, chronic and recurrent viral infections, conditions requiring detoxification, and herpes simplex virus.
Global interest in hyperthermia as a means of treating cancer was initiated by the first International Congress on Hyperthermic Oncology in Washington in 1975. In the last several decades hyperthermia has been shown to be an effective means of treating cancer either stand alone or in conjunction with other treatments such as radiotherapy or chemo-therapy.
The fact that in vivo tumour cells are more sensitive to heat than normal healthy cells has been well established [1,2]. A tumour cell killing effect is achieved at temperatures between 40 and 44 Celsius. At temperatures above 42.5-43° C. the exposure time can be halved with each 1° C. of temperature increase to give an equivalent cell kill [2]. Most normal cells and tissues are undamaged by treatment of up to 44° C. for 1 hour [3].
Hyperthermia can be induced in several different ways. Local hyperthermia can be induced by external or internal energy sources. Regional hyperthermia can be achieved by perfusion of organs or limbs or by irrigation of body cavities. Whole body hyperthermia can also be induced in patients whose cancer has spread to several different areas.
The effectiveness of hyperthermia treatment is related to the temperature achieved during the treatment, as well as the length of treatment and cell and tissue characteristics. Normal tissues are generally not damaged during hyperthermia if the temperature remains under 111° F. or 44° C. It is therefore beneficial to raise the temperature of the tumour as high as possible while limiting the temperature of surrounding healthy tissues to 44° C. or lower.
Local Hyperthermia:
With local hyperthermia, an energy source causes the temperature of a tumour to be heated and rise locally. For local hyperthermia there is little heat rise for tissues at some distance from the tumour. However, it is difficult to ensure that the entire tumour is being exposed to sufficiently high temperatures without overheating the surrounding tissues. Furthermore, if parts of the tumour are not sufficiently heated, then some cancer cells survive the treatment and they continue to multiply.
Regional Hyperthermia:
Regional hyperthermia heats a part of the body, such as an organ, limb, or body cavity. It is generally combined with chemotherapy or radiation therapy. One approach, called regional perfusion, isolates the blood supply for that part of the body and uses a heating device to warm the blood and pump it back into the area to heat it. This method is being studied to treat certain cancers in the arms or legs.
A similar technique is being tested along with surgery against cancers in the abdominal cavity. During surgery, heated chemotherapy drugs are circulated through the peritoneal cavity. This is called continuous hyperthermic peritoneal perfusion, or CHPP.
Yet another approach to regional hyperthermia is deep tissue hyperthermia. This method uses RF or Microwave radiating devices that are placed on the surface of the organ or body cavity and produce high energy waves directed at a specific area.
Whole Body Hyperthermia:
Whole body hyperthermia is also being studied as a way to make chemotherapy more effective in treating cancer that has spread (metastatic cancer). Body temperature is raised by using warm-water blankets, inductive coils (like those in electric blankets), or thermal chambers (much like large incubators).
Moderate Whole Body Hyperthermia stimulates the immune system. By raising the core body temperature to approximately 39.5° C. (103.1 F) a natural fever is simulated which in turn increased the number and activity of natural cells, T-helper cells and cytotoxic T-cells. This treatment is also used in cancer diseases with special association to the immune system like renal-cell-carcinoma, malignant melanoma and special lymphomas. This method can also be used to prevent recurrences.
Extreme whole body hyperthermia is used in a combination with chemotherapy in advanced or metastatic cancer. The body core temperature is increased up to 42° C. (107.6 F). This method is useful in advanced cancer, especially with metastases of different organs, e.g. in the liver, bones or lungs.
In combination with whole body hyperthermia, chemotherapy has been demonstrated to be more effective. The chemotherapy is started at a temperature of about 41° C. (105.8 F). Often, when combined with hyperthermia, it is possible to use very low doses of chemotherapy so side effects are kept to a minimum. Tumours or metastases resistant to chemotherapy can be successfully treated with a combination treatment of chemotherapy and whole body hyperthermia.
Hyperthermia as a Treatment for HIV/AIDS
Hyperthermia has also been studied and found to have some effectiveness in treating HIV and AIDS and potentially other infectious diseases where the virus or bacteria is sensitive to elevated temperatures. Several studies have been performed over the last decade which showed that Whole Body Hyperthermia was a promising means of treating HIV.
For example, Alonso reported the long-term results of a single session of low-flow (0.3 L/min) extracorporeal perfusion hyperthermia on 29 men and 2 women with disseminated Kaposi's sarcoma and profound immunologic impairment [4]. Antiretroviral treatment was stopped 72 hours prior to treatment and withheld during the period of follow-up. Core temperature was raised to 42 Celsius and held for 1 hour with extracorporeal perfusion and ex vivo blood heating to 49 degrees C. as the means of temperature control. Of 31 patients, 2 died of complications secondary to treatment (cardiac arrhythmia; CNS bleeding). There were two cases of intravascular coagulopathy. At 30 days post-treatment complete or partial regressions were seen in 20/29 of those treated, with regressions persisting in 14/29 of those treated by 120 days post treatment. At 360 days, 4/29 maintained tumour regressions with 1 in complete remission (at 26 months). The patient in complete remission remained culture-negative and PCR-negative for HIV and his CD4 count rose from around 250 to around 800. Selected healed lesions were biopsied to demonstrate tumour absence. Patients were selected for treatment if pre-treatment testing of the tumour showed regression in vitro with heat exposure. Analysis of the early and midterm failures showed little sustained rise of the CD4 cells if presenting total CD4 counts were below 50 and had been at such low levels for extended periods. Analysis of the tumours of the few men not responding demonstrated elevated levels of IL-6 as compared to responders (12 vs. <1 pg/ml). At 120 days 29/31 patients remained alive (expected, 20). At 360 days, 21/31 remained alive (expected, 11). In no patient was HIV activity stimulated with heat exposure. It was noted by Alonso et al. that the effectiveness of the hyperthermia to boost CD4+ lymphocytes was not significant in patients with significant immunodeficiency and very low CD4 counts while for patients which retained relatively high CD4 of 300 or greater, a significant increase was observed post treatment.
In the clinical trial conducted by Alonso and colleagues, hyperthermia was induced by using a low flow (0.3 L/min) extracorporeal perfusion heating method. A perfusion catheter was inserted into the femoral artery and vein of the opposing limb. Blood flow was propelled by the patient's own arterial pressure, to a roller pump, and was heated by a heating block to 49° C. before being reinserted into the femoral vein. Blood, rectal and intramuscular thermometers monitored patient temperatures.
Steinhart later engaged in an FDA-approved trial of hyperthermia as a means of treating HIV. Steinhart enrolled six men with CD4 counts below 200 and at least three KS lesions in the first FDA-approved trial of hyperthermia. Participants underwent one hour of whole-body hyperthermia at 40 or 42 degrees Centigrade. No adverse side-effects were observed during treatment. KS lesions partially regressed immediately following whole-body hyperthermia in all participants but returned to pre-treatment status in five people after one week. Participants experienced a significant reduction in HIV RNA immediately after cool-down in the 42 degree Centigrade treatment group which returned to pre-treatment levels after one week.
There is also a reasonably large body of research which has established the sensitivity of the HIV virus to temperature. HIV, like other enveloped viruses is temperature-sensitive and suffers greater inactivation for a given length of time as temperatures progressively increase above 37° C. [5]. Spire et al. demonstrated a 40% inactivation of HIV when maintained in a warm water bath for 30 minutes [6]. McDougal et al. demonstrated a linear log relationship of HIV kill from 37° C. to 56° C. [7]. Marcial-Vega et al. demonstrated that a 2-hour exposure of HIV to 42° C. effectively killed all free virus (to concentrations of 800 ng/ml) as well as infected cells [8]. Wong et al. found that HIV-infected cells are more sensitive to heat damage that uninfected cells and that this sensitivity was potentiated by tumour necrosis factor-a. A secondary benefit of whole body hyperthermia is the stimulation of antibody production following an elevated core body temperature [9,10]. This is potentially why CD4 counts increased following whole body hyperthermia in the Alfonso study, in patients which had an initial CD4 counts still about 200.
Based on the work cited above it seems that heat or hyperthermia is a promising approach to treating HIV. Preliminary work using whole body hyperthermia has demonstrated an ability to slow down the progression of AIDS and extend patient life, although as of yet there does not seem to be any reported cases where the virus was totally eradicated. Furthermore, a large body of work which aims to study the temperature sensitivity of HIV to temperature has shown that temperatures which are within range of whole body hyperthermia, i.e. 42° C., effectively killed all free virus as well as infected cells [8].
There is also a growing body of work which aims to leverage whole body hyperthermia for the treatment of hepatitis C. In 2002, the Netherlands Liver Foundation (NLF) initiated a clinical trial to evaluate whole body hyperthermia as a means of treating hepatitis C. The trial was conducted at the Utrecht Medical Centre in Hepatology. The rational for using whole body hyperthermia for treating hepatitis C are similar to HIV. The elevated temperatures preferentially kill HVC virus and a secondary benefit is achieved since, as discussed above, hyperthermic temperatures have been shown to stimulating the immune system.
Other Diseases
It should also be noted that hyperthermia could also be used to treat other diseases. Any infectious disease where the pathogen is found to be adversely affected by elevated temperature could potentially be treated by hyperthermia. Furthermore, given that the immune system is stimulated by an elevated core body temperature, a secondary benefit could be produced even for infectious diseases which are not sensitive to temperature.
Thus in summary, it has been shown that whole body hyperthermia could be induced up to temperatures of about 42° C. Core body temperatures of up to 42° C. or in some cases as low as 39° C. were found to be effective at treating cancer, HIV, Hepatitis C and other infectious or chronic diseases. Much research has been performed on using hyperthermia as a treatment for cancer, while its use for HIV treatment is a fairly new area which has shown some promising results. Hyperthermia has also been used to treat chronic inflammatory conditions such as ulcerative colitis and Crohn's disease, rheumatic conditions, bronchial asthma, chronic and recurrent viral infections and even conditions requiring detoxification.
Nevertheless, it is also known that during hypothermic or hyperthermic procedures, the brain is more sensitive to changes in temperature than most other parts the body. While in some circumstances, the brain has been found to withstand an extended period of hypothermia, as low as 30° C., i.e. about 7° C. below normal body temperature, it is also well known that the brain is much less able to withstand similar temperature differentials above normal, or even extended periods of hyperthermia above 42° C., without risk of significant damage or life-threatening effects. Studies have shown that the human brain begins to show damage when the core temperature reaches 41° C. Damage to the brain, as well as the physiological response induced by the hypothalamus, are key limitations to raising human body temperature above 42° C.
Thus, during hyperthermic treatment for cancer, HIV or other conditions, it is desirable to protect the patient's brain from detrimental effects of hyperthermia.
By way of example, systems for whole body thermotherapy are disclosed, in U.S. Pat. No. 5,817,045 to Sever, entitled “Apparatus and method for enabling extracorporeal therapy of up to at least one half of a living patient's entire circulating blood supply during a continuous time interval” and in U.S. Pat. No. 5,074,838 to Kroyer et al. entitled “Extracorporal thermo-therapy device and method for curing diseases using penetrants.”
U.S. Pat. No. 7,241,307 to Lennox, entitled “Method and Apparatus for Managing Temperature in a Patient” discloses localized cooling of the head for hypothermia treatments only, e.g. for treating brain injury, stroke, or during cardiac arrest, using a single catheter system to withdraw, cool and then reinject a portion of blood in a reciprocating fashion, providing limited temperature control. For elevated hyperthermia treatment as described above, such as system would be problematical, because heated blood flow from the body would enter the brain directly during the intake stroke of the pump, with potentially detrimental effects.
U.S. Pat. No. 6,669,661 to Yee entitled “Method and device for central nervous system protection during whole body hyperthermia or hypothermia”, for example, discloses a system and method that attempts to address the problem of protecting the brain and nervous system from the effects of hyperthermia. Not only is this system is complex and expensive, but the procedure involves anaesthesia and complete separation CNS circulation from the rest of the body, with associated risks to the patient.
For prolonged hyperthermic treatments, it is desirable to avoid such extreme intervention, and, for example, enable treatment of a conscious patient with minimal disruption of normal blood circulation, while protecting the brain from excessive temperatures.
Thus improved apparatus, systems and methods are required for extracorporeal blood processing for establishing and maintaining hyperthermia for diagnostic and therapeutic treatments.
The present invention seeks to overcome, or at least ameliorate, one or more of the disadvantages of known apparatus, systems and methods, or at least provide an alternative.